Age-related macular degeneration (AMD) and other retinal degenerative diseases remain among the greatest challenges to public health, and innovative approaches to understand disease mechanisms are needed. The functional integrity of the retinal pigment epithelial and photoreceptor cells (RPE/PRC) are tightly interrelated and regulated to ensure vision. Docosahexaenoic acid (22: 6n-3, DHA), which attains its highest concentrations in the body in PRC outer segments, in which it is avidly retained and conserved, plays a critical role in sustaining RPE/PRC integrity. Under conditions of uncompensated oxidative stress (OS), neuroprotectin D1 (NPD1), a cell survival mediator, is made on-demand from DHA when disruptors of homeostasis evolve, and the initial inflammatory response needs to be modulated to protect RPE/RPC integrity. Our broad goal is to understand the molecular principles underlying DHA retention/conservation and NPD1-mediated protection under stress. Results during the recent funding period provide some strong clues to these principles, as they reveal an unexpected mechanism critical for DHA retention/conservation, as well as a novel connection between NPD1 and transcriptional regulation. Thus, our immediate goal is to further define the genetic and cellular mechanisms that govern pro-survival mechanisms, as well as the proteins that carry out these important protective actions. The three Aims for the next grant period are directed at testing specific predictions based on the following hypothesis: RPE/PRC integrity is sustained via the pivotal role of the protein adiponectin receptor 1 (AdipoR1, hereto unrecognized in these cells) in the retention and conservation functions of DHA. More specifically, AdipoR1 facilitates the synthesis of very long chain-polyunsaturated fatty acid and NPD1 availability that, in turn, modulate RPE preconditioning, Alu-RNA- induction of the NALP3 inflammasome, and cRel/BIRC3 transcription to sustain RPE/PRC integrity. Aim 1: To test the prediction, and define the molecular principles, whereby AdipoR1 is decisive for DHA retention and function in RPE and photoreceptor cells. We propose that a mechanism retains/conserves DHA, and that its ablation leads to retinal degeneration. This will allow us to address how RPE/PRC functional integrity is sustained. Aim 2: To test the prediction that Alu-induction of the NALP3 inflammasome is modulated by AdipoR1-dependent and NPD1-mediated cRel-BIRC3 expression, which are decisive for RPE cell integrity. Aim 3: To test the hypothesis that AdipoR1 mediates NPD1 induction of preconditioning (pre-C) and RPE cell survival. Thus NPD1 induces preconditioning and selectively upregulates BIRC3 expression upon oxidative stress and cREL mediates NPD1 signaling activation of BIRC3 expression and preconditioning-mediated RPE/PRC survival. The outcomes of these studies may lead to novel strategies for enhancing the intrinsic potential of RPE/PRC to protect and repair them and for promoting long-term expression of proteins involved in RPE/PRC survival.